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Cannabis use alters DNA methylation, with implications beyond smoking effects

In a recent study published within the journal Molecular Psychiatry, a team of researchers conducted a large-scale meta-analysis consisting of an epigenome-wide association study to grasp whether lifetime use of cannabis was linked to deoxyribonucleic acid (DNA) methylation observed in peripheral blood.



Study: Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use. Image Credit: Juan Gaertner / Shutterstock

Background

With an increasing variety of states in the USA (U.S.), in addition to countries internationally legalizing the medicinal use of cannabis, cannabis usage has grow to be exceedingly prevalent. Nevertheless, while the therapeutic advantages of cannabis through medicinal use have been well-studied, its recreational use also raises quite a few concerns, especially regarding problems related to addiction, cognitive deficits, and mental health disorders corresponding to depression, anxiety, psychosis, mania, and schizophrenia.

DNA methylation is an indicator of the impact of environmental aspects on health, and a few types of DNA methylation on account of environmental aspects are long-lasting, while others are transient. It occurs when a methyl group gets added to the fifth carbon of cytosine in regions with cytosine and guanine (CpG) repeats. Studies have reported that cigarette smoking ends in each persistent and transient DNA methylation at CpG sites across the genome. DNA methylation patterns in specific genes have also been observed in groups corresponding to adolescents who ceaselessly use cannabis and patients who’re depending on cannabis.

Concerning the study

In the current study, the team built on the methods from their previous study, where they performed the primary epigenome-wide association study using peripheral blood samples and investigated a big study population consisting of seven cohorts of people of various ancestries. They examined the association between lifetime cannabis use and DNA methylation patterns while adjusting for aspects corresponding to age, sex, technical covariates, blood cell proportions, and cigarette smoking behavior.

The information was obtained from seven cohorts that participated within the study, spanning diverse study groups corresponding to twins, older adults, parents and kids, and adult twins. The ultimate study population comprised 4,190 individuals who reported using cannabis of their lifetime and 5,246 individuals who had never used cannabis of their lifetime, constituting a complete of 9,436 participants. Cannabis use was characterised based on reports by the participants or parents, and a person with a minimum of 1 cannabis use event before the gathering of peripheral blood samples was defined as an ever-user.

DNA methylation was measured within the peripheral blood samples, and the β-values, which is the proportion of methylated DNA on the targeted CpG sites, were calculated. The association between lifetime cannabis use and DNA methylation levels was tested using linear models or a generalized estimating equations model in cohorts where the participants were related. The epigenome-wide association study analyses were stratified in keeping with the European-American and African-American genetic ancestry groups, and the analyses were adjusted for sex, age, cigarette smoking, and blood cell type estimates.

The meta-analysis summarized the ancestry and cohort-specific results from the epigenome-wide association study, and statistical analyses were conducted to evaluate. The methylation rating, which is the weighted sum of the CpG sites significantly linked to cannabis use, was also calculated. Moreover, DNA methylation correlations between whole blood and regions of the brain, corresponding to the prefrontal cortex, cerebellum, superior temporal gyrus, and entorhinal cortex were examined.

Results

The outcomes reported that 4 CpG sites showed significant associations with cannabis use, and these included CpG sites within the disintegrin and metalloprotease 12 (ADAM12) and alpha-actinin 1 (ACTN1) genes and near the adhesion G protein-coupled receptor F1 (ADGRF1) gene and long noncoding ribonucleic acid (RNA) LINC01132.

The essential model of the epigenome-wide association study indicated that cannabis use was related to DNA methylation in CpG sites that largely overlapped with those linked to cigarette smoking. Nevertheless, adjusting for cigarette smoking behavior identified one other CpG site related to cannabis use within the apolipoprotein B receptor (APOBR) gene.

The five genes containing DNA-methylated CpG sites related to cannabis use have significant roles in various health outcomes. LINC01132 functions as an oncogene and is linked to malignancy in hepatocellular carcinoma and ovarian cancer, although cannabis use has been reported to lower the incidence of hepatocellular carcinomas. Genetic variation within the ACTN1 gene, which encodes the cytoskeletal protein that binds actin fibers to cell membranes, has been linked to numerous diseases corresponding to Bowen disease, Angelman syndrome, lupus erythematosus, and congenital macrothrombocytopenia, in addition to coronavirus disease 2019 (COVID-19).

Conclusions

Overall, the findings reported substantial DNA methylation changes in CpG sites across five genes that play significant roles in health and disease. While 4 of those CpG sites overlap with those related to cigarette smoking, cannabis use by itself can be linked to DNA methylation in a single gene. The outcomes highlight the utility of DNA methylation as a tool to grasp the interactions between environmental aspects and genetics and emphasize the necessity for further research on the impact of cannabis use on health outcomes.

Journal reference:

  • Fang, F., Quach, B., Lawrence, K. G., Dongen, van, Marks, J. A., Lundgren, S., Lin, M., Odintsova, V. V., Costeira, R., Xu, Z., Zhou, L., Mandal, M., Xia, Y., Vink, J. M., Bierut, L. J., Ollikainen, M., Taylor, J. A., Bell, J. T., Kaprio, J., & Boomsma, D. I. (2023). Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use. Molecular Psychiatry. https://doi.org/10.1038/s4138002302310w, https://www.nature.com/articles/s41380-023-02310-w  
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